WO2008033810A2 - Method for the synthesis of basic chromium carboxylates - Google Patents
Method for the synthesis of basic chromium carboxylates Download PDFInfo
- Publication number
- WO2008033810A2 WO2008033810A2 PCT/US2007/078123 US2007078123W WO2008033810A2 WO 2008033810 A2 WO2008033810 A2 WO 2008033810A2 US 2007078123 W US2007078123 W US 2007078123W WO 2008033810 A2 WO2008033810 A2 WO 2008033810A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carboxylate
- metal
- iii
- hydroxide
- chromium
- Prior art date
Links
- 239000011651 chromium Substances 0.000 title claims abstract description 71
- 229910052804 chromium Inorganic materials 0.000 title claims abstract description 40
- 238000000034 method Methods 0.000 title claims abstract description 35
- -1 chromium carboxylates Chemical class 0.000 title claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 16
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims abstract description 36
- BFGKITSFLPAWGI-UHFFFAOYSA-N chromium(3+) Chemical class [Cr+3] BFGKITSFLPAWGI-UHFFFAOYSA-N 0.000 claims abstract description 17
- 150000007942 carboxylates Chemical class 0.000 claims abstract description 16
- 229910000000 metal hydroxide Inorganic materials 0.000 claims abstract description 12
- 150000004692 metal hydroxides Chemical class 0.000 claims abstract description 12
- 239000006227 byproduct Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 9
- 239000011541 reaction mixture Substances 0.000 claims abstract description 8
- 125000005599 alkyl carboxylate group Chemical group 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 239000000047 product Substances 0.000 claims abstract description 5
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 3
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 229910021556 Chromium(III) chloride Inorganic materials 0.000 claims description 7
- 239000011636 chromium(III) chloride Substances 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- 235000019260 propionic acid Nutrition 0.000 claims description 7
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 12
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- 238000010992 reflux Methods 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- VQWFNAGFNGABOH-UHFFFAOYSA-K chromium(iii) hydroxide Chemical compound [OH-].[OH-].[OH-].[Cr+3] VQWFNAGFNGABOH-UHFFFAOYSA-K 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 231100000331 toxic Toxicity 0.000 description 6
- 230000002588 toxic effect Effects 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 230000037213 diet Effects 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 230000009471 action Effects 0.000 description 4
- PHFQLYPOURZARY-UHFFFAOYSA-N chromium trinitrate Chemical compound [Cr+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O PHFQLYPOURZARY-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 235000015872 dietary supplement Nutrition 0.000 description 4
- 201000010063 epididymitis Diseases 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 150000003841 chloride salts Chemical class 0.000 description 2
- 229940117975 chromium trioxide Drugs 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- JOPOVCBBYLSVDA-UHFFFAOYSA-N chromium(6+) Chemical class [Cr+6] JOPOVCBBYLSVDA-UHFFFAOYSA-N 0.000 description 2
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001550 testis Anatomy 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 235000021411 American diet Nutrition 0.000 description 1
- 229910021555 Chromium Chloride Inorganic materials 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001450 anions Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- 231100000505 clastogenic Toxicity 0.000 description 1
- 230000003541 clastogenic effect Effects 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000006052 feed supplement Substances 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 108091005995 glycated hemoglobin Proteins 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000010983 kinetics study Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical class OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- AKMJJGSUTRBWGW-UHFFFAOYSA-N pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC=N1.OC(=O)C1=CC=CC=N1 AKMJJGSUTRBWGW-UHFFFAOYSA-N 0.000 description 1
- YVVONORJTFWCED-UHFFFAOYSA-N pyridine-2-carboxylic acid pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1.OC(=O)C1=CC=CC=N1 YVVONORJTFWCED-UHFFFAOYSA-N 0.000 description 1
- AKGNIBXGIPMDLE-UHFFFAOYSA-N pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=C1.OC(=O)C1=CC=NC=C1 AKGNIBXGIPMDLE-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229910001428 transition metal ion Inorganic materials 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table
- C07F11/005—Compounds containing elements of Groups 6 or 16 of the Periodic Table compounds without a metal-carbon linkage
Definitions
- the present invention relates to a method for the synthesis of chromium complexes of formula [Cr 3 O(carboxylate) 6 (H 2 O) 3 ] + , wherein the synthesis uses simple and inexpensive starting materials and no organic solvents, and can be performed while generating little or no toxic by-products.
- Such materials also have potential as insulin- potentiating therapeutics which could possibly see use in the treatment of diabetes and related conditions [H]. Determining the structure, function, and mode of action of the biologically active form of chromium could greatly aid in the rational design of such potential therapeutics.
- the first chromium-containing species proposed to be biologically active was glucose tolerance factor(GTF)[l,12].
- GTF glucose tolerance factor
- GTF was first isolated from acid-hydrolyzed porcine kidney powder, although a similar, if not identical, material was subsequently isolated from yeast[l,13].
- yeast Currently the term GTF is usually understood to refer to only the material isolated from yeast.
- GTF is absorbed better than simple chromic salts and potentiates insulin action in rat epididymal tissue or isolated rat adipocytes [14].
- kinetics studies indicate that GTF does not intrinsically possess biological activity [15]; additionally, the material is apparently a byproduct of the acid hydrolysis step used in its purification [16].
- GTF was proposed to be composed of chromic ion, nicotinic acid, and the amino acids glycine, glutamic acid and cysteine [13]. While these results have not been reproducible in some laboratories [17-21], this report stimulated an intense interest in the synthesis of chromic-nicotinate complexes [22-25], some of which have been patented as nutritional supplements.
- the proposed identification of nicotinic acid (2-carboxypyridine) also stimulated investigations of complexes of chromium(III) with the related pyridine carboxylic acids picolinic acid (2-carboxypyridine) and isonicotinic acid (4-carboxypyridine) [26-28].
- chromium(ITf) tris(picolinate), Cr(pic) 3 has become a very popular nutritional supplement and is being tested as a therapeutic for the treatment of symptoms of adult-onset diabetes. It is available over-the-counter in the form of pills, chewing gums, sport drinks, and nutrition bars. Cr(pic) 3 has been proposed to be the biologically active form of chromium [29]. This is, however, extremely doubtful given the chemistry required to synthesize this material.
- the compound and other chromium sources examined also had no effect on body mass, percentage lean or fat content, tissue size (heart, testes, liver, kidney, muscle, epididymal fat, spleen, and kidney), or blood variables (fasting glucose, insulin, cholesterol, etc.). No differences in the gross histology of the liver or kidney (organs where chromium(i ⁇ ) preferentially accumulated) were found, although chromium did accumulate in these organs [33].
- Another study compared the effects of a Cr-deficient diet with diets supplemented with ten different sources of chromium, including allowing rats to live in stainless steel cages.
- the Cr sources had no effect on body mass; all but one source decreased epididymal fat. Testes and liver masses tended to be lowered, whereas kidney, heart, and spleen masses were not significantly altered. Supplemental Cr had no effect on serum triglycerides or cholesterol, and only one source resulted in lower serum glucose [34]. While these studies did not manifest any acute toxicity, the lack of beneficial effects of Cr(pic) 3 supplementation on growth, fat content or glucose, insulin, or cholesterol concentrations raises questions about its therapeutic potential. Recently the safety of intaking Cr(pic) 3 has been questioned, especially in regards to its potential to cause clastogenic damage [35,36].
- Cr(pic) 3 has been shown to catalytically produce hydroxyl radicals which cleave DNA[35]. This ability stems from the combination of chromium and picolinate; the picolinate ligands prime the redox potential of the chromic center such that it is susceptible to reduction. The reduced chromium species interacts with dioxygen to produce reduced oxygen species including hydroxyl radical.
- Freshly prepared chromic hydroxide is a very fine powder, which is very difficult to filter on a laboratory scale and should be extraordinarily difficult to filter to isolate on an industrial scale. Additionally, the filtrate, which could potentially be recycled to some degree, is an extremely caustic solution.
- Antsyshkina and coworkers prepared Cr3 by heating a mixture of chromium nitrate and propionic anhydride; the mixture was heated until toxic, noxious fumes of nitrogen oxide, NO x , appeared. Finally, following the procedure developed by Vincent and coworkers for making basic chromium carboxylates in nonaqueous solvents [45], Fujihara, et al. [46] prepared Cr3 from chromium nitrate and propionic acid in acetone.
- one object of the present invention is to provide a method for synthesis of chromium complex 2
- a further object of the present invention is to provide a method for synthesis of chromium complex 2 that uses no organic solvents and uses simple and inexpensive starting materials.
- a further object of the present invention is to provide a method for synthesis of chromium complex 2 that can be performed in one pot, in essentially one step.
- the present invention relates to a method for synthesis of chromium complex 2, [Cr 3 O(carboxylate) 6 (H 2 O) 3 ] + (2), wherein carboxylate is a substituted or unsubstituted C2-C5 alkyl carboxylate.
- carboxylate group is acetic, propionic, n-butyric or n- pentanoic, most preferably propionic (thus resulting in Complex 1, [Cr 3 O(O 2 CCH 2 CH 3 ) 6 (H 2 O) 3 ] + , noted above, called Cr3).
- Complex 1 has been shown in healthy and model type 2 diabetic rats to increase insulin sensitivity and improve blood plasma cholesterol and triglycerides levels and to reduce glycated hemoglobin in the diabetes models. Complex 1 has also been shown to reduce the onset of colorectal cancer in rat. Complex 1 is absorbed very rapidly and very efficiently compared to other chromium-containing nutritional supplements. It also dissolves in water very rapidly.
- a chromium(III) salt such as CrCl 3 6H 2 O
- a substituted or unsubstituted C2-C5 alkyl carboxylic acid, sodium hydroxide and water (or an aqueous solution of the last two) are combined in a reaction vessel.
- This is preferably heated under reflux conditions until a dark green color develops. Allowing the solution to cool produces a green solid or oil of the corresponding salt of the chromium complex 2, which is isolated by filtration or by decanting the solution above the oil.
- the filtrate is a dark blue solution comprised of other chromium carboxylate complexes, water, carboxylic acid, and sodium chloride. This material, comprised of harmless byproducts, can be recycled to subsequent reaction mixtures to obtain more yield of the chromium complex 2.
- chromium complex 2 which can be used without filtration or decanting as a liquid form of the chromium complex 2, particularly for feed supplement applications such as spraying into animal feed, etc.
- the chromium (ITl) salt can be any Cr(IH) salt.
- X is an anion, which when combined with the metal M of the hydroxide source in the reaction, generates a water-soluble MX compound.
- X is halogen, substituted or unsubstituted C2-C5 alkyl carboxylate (wherein the substituents can be selected from the same substituents described below for the alkyl carboxylic acid component).
- M is a metal cation, which when combined with a hydroxide anion, generates a water- soluble metal hydroxide.
- M is an alkali metal or alkaline earth metal, more preferably sodium or potassium or calcium, most preferably sodium.
- the alkyl carboxylic acid is any unsubstituted C2-C5 alkyl carboxylic acid or substituted C2-C5 alkyl carboxylate.
- Suitable substituents are any substituent that does not interfere with the reaction to provide the basic chromium complex, including but not limited to, C1-C4 alkoxy, and halogen.
- the alkyl carboxylic acid is acetic acid, propionic acid, n-butyric acid or n-pentanoic acid, most preferably propionic acid. These acids would respectively result in the chromium complex 2 wherein the carboxylate group is, respectively, acetic, propionic, n-butyric or n-pentanoic, most preferably propionic.
- the balanced reaction stated above indicates particular molar ratios of starting materials (i.e. 1:2:2 Cr(III) saltalkyl carboxylic acid:metal hydroxide), the molar ratios can vary as desired in order to achieve optimum reaction.
- the molar ratio of Cr(i ⁇ ) salt to alkyl carboxylic acid is in a range of from 1 :2 to 1 : 100, most preferably 1 :2.
- the molar ratio of Cr(III) salt to metal hydroxide is in a range of from 1 :2 to 1:3, most preferably 1 :2.
- the reaction mixture is aqueous with the Cr(III) salt being present in a molar concentration of from 1-3 molar, based on the amount of water in the mixture.
- the other starting materials are adjusted according to the desired ratios relative to Cr(IH) salt.
- the reaction is performed for a time period and at a temperature sufficient to produce the chromium complex 2, the production of which is signified by a color change in the reaction mixture from a blue-green/green-blue color to a dark green color.
- the time period is from 10 minutes to 3 hours.
- the temperature is generally the reflux temperature of the reaction mixture. In the case of aqueous mixtures, this is generally within about 1O 0 C of 100 0 C (the boiling point of water).
- temperatures below the reflux temperature provided that the reaction time is increased to permit reaction to go to completion. Accordingly, temperatures from 35°C to reflux of the solution can be used, preferably 4O 0 C to reflux, more preferably 50 0 C to reflux, most preferably within 10 0 C of the reflux temperature of the solution.
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Abstract
A method for the synthesis of a chromium complex 2, [Cr3O(carboxylate)6(H2O)3]+ (2), wherein carboxylate is a substituted or unsubstituted C2-C5 alkyl carboxylate, is provided, including the step of : heating an aqueous reaction mixture of a Cr(III) salt, a substituted or unsubstituted C2-C5 alkyl carboxylic acid and a metal hydroxide for a time period and at a temperature sufficient to generate an aqueous product mixture comprising chromium complex 2 and non toxic byproducts.
Description
TITLE OF THE INVENTION
METHOD FOR THE SYNTHESIS OF BASIC CHROMIUM CARBOXYLATES
BACKGROUND OF THE INVENTION Field of Invention
The present invention relates to a method for the synthesis of chromium complexes of formula [Cr3O(carboxylate)6 (H2O)3 ]+, wherein the synthesis uses simple and inexpensive starting materials and no organic solvents, and can be performed while generating little or no toxic by-products.
Discussion of the Background hi the late 1950s and 1960s, rats fed a chromium-deficient diet were found to possess an apparent decreased ability to repress blood glucose concentrations, while chromic ions were shown to increase the efficiency of insulin action in rat epididymal tissue [1-5]. Since these observations, a search has been underway to identify the biologically active form of chromium, that is, the biomolecule which naturally binds chromium (III) and possesses an intrinsic function associated with insulin action in mammals [6-8]. The average American diet contains only about 30 μg Cr per day [9, 10], which has resulted in the development of chromium-containing dietary supplements. Such materials also have potential as insulin- potentiating therapeutics which could possibly see use in the treatment of diabetes and related conditions [H]. Determining the structure, function, and mode of action of the biologically active form of chromium could greatly aid in the rational design of such potential therapeutics.
The first chromium-containing species proposed to be biologically active was glucose tolerance factor(GTF)[l,12]. GTF was first isolated from acid-hydrolyzed porcine kidney powder, although a similar, if not identical, material was subsequently isolated from yeast[l,13]. Currently the term GTF is usually understood to refer to only the material isolated from yeast. GTF is absorbed better than simple chromic salts and potentiates insulin action in rat epididymal tissue or isolated rat adipocytes [14]. However, kinetics studies
indicate that GTF does not intrinsically possess biological activity [15]; additionally, the material is apparently a byproduct of the acid hydrolysis step used in its purification [16].
GTF was proposed to be composed of chromic ion, nicotinic acid, and the amino acids glycine, glutamic acid and cysteine [13]. While these results have not been reproducible in some laboratories [17-21], this report stimulated an intense interest in the synthesis of chromic-nicotinate complexes [22-25], some of which have been patented as nutritional supplements. The proposed identification of nicotinic acid (2-carboxypyridine) also stimulated investigations of complexes of chromium(III) with the related pyridine carboxylic acids picolinic acid (2-carboxypyridine) and isonicotinic acid (4-carboxypyridine) [26-28]. As a result chromium(ITf) tris(picolinate), Cr(pic)3, has become a very popular nutritional supplement and is being tested as a therapeutic for the treatment of symptoms of adult-onset diabetes. It is available over-the-counter in the form of pills, chewing gums, sport drinks, and nutrition bars. Cr(pic)3 has been proposed to be the biologically active form of chromium [29]. This is, however, extremely doubtful given the chemistry required to synthesize this material.
In the last decade, a number of investigators have examined the effects of administering Cr(pic)3 (and in some cases other forms of chromium(iπ)) to rats on regular diets [30-33]. After an initial preliminary report which suggested beneficial effects on blood variables [30], detailed examinations of the effect of Cr(pic)3 administration in amounts up to 1500 μg/kg diet for up to 24 weeks have found no acute toxic effects [31-33]. However, the compound and other chromium sources examined (most notably "Cr nicotinate" and chromium chloride) also had no effect on body mass, percentage lean or fat content, tissue size (heart, testes, liver, kidney, muscle, epididymal fat, spleen, and kidney), or blood variables (fasting glucose, insulin, cholesterol, etc.). No differences in the gross histology of the liver or kidney (organs where chromium(iπ) preferentially accumulated) were found, although chromium did accumulate in these organs [33]. Another study compared the effects of a Cr-deficient diet with diets supplemented with ten different sources of chromium, including allowing rats to live in stainless steel cages. The Cr sources had no effect on body mass; all but one source decreased epididymal fat. Testes and liver masses tended to be lowered, whereas kidney, heart, and spleen masses were not significantly altered. Supplemental Cr had no effect on serum triglycerides or cholesterol, and only one source
resulted in lower serum glucose [34]. While these studies did not manifest any acute toxicity, the lack of beneficial effects of Cr(pic)3 supplementation on growth, fat content or glucose, insulin, or cholesterol concentrations raises questions about its therapeutic potential. Recently the safety of intaking Cr(pic)3 has been questioned, especially in regards to its potential to cause clastogenic damage [35,36]. At physiologically-relevant concentrations of chromium (120 iiM) and biological reductants such as ascorbic acid and thiols (5 mM), Cr(pic)3 has been shown to catalytically produce hydroxyl radicals which cleave DNA[35]. This ability stems from the combination of chromium and picolinate; the picolinate ligands prime the redox potential of the chromic center such that it is susceptible to reduction. The reduced chromium species interacts with dioxygen to produce reduced oxygen species including hydroxyl radical. These studies are in agreement with earlier studies which showed that mutagenic forms of chromium(III) required chelating ligands containing pyridine-type nitrogens coordinated to the metal [37].
Cr3 and other compounds of the general formula [Cr3O(O2CR)6L3]"* (where M is a trivalent transition metal ion, R is an organic group, and L is a terminal ligand such as water or pyridine) are called basic chromium carboxylates. [For Cr3, R=Et, L=H2O, and n=l Complex 1] . They historically have been prepared by "three general methods: reaction of freshly precipitated chromium(III) hydroxide with the carboxylic acid, either neat or in aqueous solution; reduction of chromium trioxide in the acid media, the reductant being the acid itself (acetic or formic), or some added substance such as ethanol; and oxidation of chromium(II) carboxylates." [38] In terms of synthesizing Cr3 or any of these on an industrial scale, all of these avenues are problematic. Cr(II) compounds are air sensitive and would require specialized equipment. Chromium trioxide and other Cr(VI) complexes are carcinogenic; the possibility of incomplete reduction could represent a health risk. Freshly prepared chromic hydroxide is a very fine powder, which is very difficult to filter on a laboratory scale and should be extraordinarily difficult to filter to isolate on an industrial scale. Additionally, the filtrate, which could potentially be recycled to some degree, is an extremely caustic solution.
For Cr3 specifically, a few syntheses have been described in the literature. The first reported synthesis of Cr 3 dates back to 1908 by A. Werner [39]; Werner started from chromic hydroxide, although the formula for the chloride salt of Cr3 was incorrectly reported as
[Cr3(OH)2(propionate)6]Cl 5H2O, although this is remarkably close to the correct [Cr3O(propionate)6(H2O)3]Cl (H2O)n, especially given the resources available at the time. Weinland and Hoehn apparently also made Cr3 from Cr(VI) in 1911 [40]. Another reported synthesis of Cr3 in English appeared in 1966 by Eamshaw and coworkers, although the cation was still incorrectly identified as [Cr3(OH)2(propionate)e]+ [41]. They basically used the chromic hydroxide procedure of Werner. The use of chromic hydroxide to generate Cr3 was also reported by Szymanska-Buzar and Ziolowski [42]; their procedure was a simple variation on that of Werner. Kapoor and Sharma [43] reported synthesizing Cr3 from anhydrous CrCl3 and propionic acid in CCl4, starting at -1O0C and then heating the reaction to reflux with the generation of HCl. The use of an organic solvent, especially a carcinogen, is less than ideal, as is the generation of HCl. Antsyshkina and coworkers [44] prepared Cr3 by heating a mixture of chromium nitrate and propionic anhydride; the mixture was heated until toxic, noxious fumes of nitrogen oxide, NOx, appeared. Finally, following the procedure developed by Vincent and coworkers for making basic chromium carboxylates in nonaqueous solvents [45], Fujihara, et al. [46] prepared Cr3 from chromium nitrate and propionic acid in acetone.
Thus, all synthetic procedures for preparing Cr3 to date involve the use of nonaqueous solvents, the formation difficult to isolate chromic hydroxide as an intermediate, or the production of toxic or hazardous byproducts. A one-pot, aqueous synthesis of Cr 3 and related complexes without the production of toxic byproducts, which can be scaled from the laboratory to an industrial setting, is needed.
References
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SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide a method for synthesis of chromium complex 2
[Cr3θ(carboxylate)e(H2O)3]+ (2), which is readily scaled to industrial scale and produces little or no toxic by-products.
A further object of the present invention is to provide a method for synthesis of chromium complex 2 that uses no organic solvents and uses simple and inexpensive starting materials.
A further object of the present invention is to provide a method for synthesis of chromium complex 2 that can be performed in one pot, in essentially one step. These and further objects of the present invention have been satisfied, either individually or in combinations, by the discovery of a method for the synthesis of a chromium complex 2, [Cr3O(carboxylate)6(H2O)3]+ (2), wherein carboxylate is a substituted or unsubstituted C2-C5 alkyl carboxylate, comprising: heating an aqueous reaction mixture of a Cr(III) salt, a substituted or unsubstituted C2-C5 alkyl carboxylic acid and a metal hydroxide for a time period and at a temperature sufficient to generate an aqueous product mixture comprising chromium complex 2 and nontoxic byproducts.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method for synthesis of chromium complex 2, [Cr3O(carboxylate)6(H2O)3]+ (2), wherein carboxylate is a substituted or unsubstituted C2-C5 alkyl carboxylate. Preferably the carboxylate group is acetic, propionic, n-butyric or n-
pentanoic, most preferably propionic (thus resulting in Complex 1, [Cr3O(O2CCH2CH3)6(H2O)3]+, noted above, called Cr3).
Complex 1 has been shown in healthy and model type 2 diabetic rats to increase insulin sensitivity and improve blood plasma cholesterol and triglycerides levels and to reduce glycated hemoglobin in the diabetes models. Complex 1 has also been shown to reduce the onset of colorectal cancer in rat. Complex 1 is absorbed very rapidly and very efficiently compared to other chromium-containing nutritional supplements. It also dissolves in water very rapidly.
In the method of the present invention, a chromium(III) salt [such as CrCl3 6H2O], a substituted or unsubstituted C2-C5 alkyl carboxylic acid, sodium hydroxide and water (or an aqueous solution of the last two) are combined in a reaction vessel. This is preferably heated under reflux conditions until a dark green color develops. Allowing the solution to cool produces a green solid or oil of the corresponding salt of the chromium complex 2, which is isolated by filtration or by decanting the solution above the oil. The filtrate is a dark blue solution comprised of other chromium carboxylate complexes, water, carboxylic acid, and sodium chloride. This material, comprised of harmless byproducts, can be recycled to subsequent reaction mixtures to obtain more yield of the chromium complex 2.
Alternatively, addition of water to the reaction product before filtration or decanting yields a solution, primarily of chromium complex 2, which can be used without filtration or decanting as a liquid form of the chromium complex 2, particularly for feed supplement applications such as spraying into animal feed, etc.
The balanced reaction is
3CrX3 + 6 (alkyl carboxylic acid) + 6MOH -> [Cr3O(carboxylate)6(H2O)3]X + 6MX + 2HX + 2H2O where X, M and alkyl carboxylic acid are as described below.
hi the present method, the chromium (ITl) salt can be any Cr(IH) salt. In particular, in the balanced reaction above, X is an anion, which when combined with the metal M of the hydroxide source in the reaction, generates a water-soluble MX compound. Preferably X is halogen, substituted or unsubstituted C2-C5 alkyl carboxylate (wherein the substituents can
be selected from the same substituents described below for the alkyl carboxylic acid component).
M is a metal cation, which when combined with a hydroxide anion, generates a water- soluble metal hydroxide. Preferably, M is an alkali metal or alkaline earth metal, more preferably sodium or potassium or calcium, most preferably sodium.
The alkyl carboxylic acid is any unsubstituted C2-C5 alkyl carboxylic acid or substituted C2-C5 alkyl carboxylate. Suitable substituents are any substituent that does not interfere with the reaction to provide the basic chromium complex, including but not limited to, C1-C4 alkoxy, and halogen. Preferably the alkyl carboxylic acid is acetic acid, propionic acid, n-butyric acid or n-pentanoic acid, most preferably propionic acid. These acids would respectively result in the chromium complex 2 wherein the carboxylate group is, respectively, acetic, propionic, n-butyric or n-pentanoic, most preferably propionic.
Although the balanced reaction stated above indicates particular molar ratios of starting materials (i.e. 1:2:2 Cr(III) saltalkyl carboxylic acid:metal hydroxide), the molar ratios can vary as desired in order to achieve optimum reaction. Preferably the molar ratio of Cr(iπ) salt to alkyl carboxylic acid is in a range of from 1 :2 to 1 : 100, most preferably 1 :2. Preferably the molar ratio of Cr(III) salt to metal hydroxide is in a range of from 1 :2 to 1:3, most preferably 1 :2. The reaction mixture is aqueous with the Cr(III) salt being present in a molar concentration of from 1-3 molar, based on the amount of water in the mixture. The other starting materials are adjusted according to the desired ratios relative to Cr(IH) salt.
The reaction is performed for a time period and at a temperature sufficient to produce the chromium complex 2, the production of which is signified by a color change in the reaction mixture from a blue-green/green-blue color to a dark green color. Preferably the time period is from 10 minutes to 3 hours. The temperature is generally the reflux temperature of the reaction mixture. In the case of aqueous mixtures, this is generally within about 1O0C of 1000C (the boiling point of water). However, it is also possible to conduct the reaction at temperatures below the reflux temperature, provided that the reaction time is increased to permit reaction to go to completion. Accordingly, temperatures from 35°C to
reflux of the solution can be used, preferably 4O0C to reflux, more preferably 500C to reflux, most preferably within 100C of the reflux temperature of the solution.
Having generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.
EXAMPLE
13.00 g (0.04879 moles) CrCl36H2O, 10.00 mL propionic acid (0.134 moles), 4.01 g (0.100 moles) NaOH, and 24.0 mL H2O are added in order to a round bottom flask equipped with a magnetic stir bar. The mixture is heated to reflux with stirring for ~2 hours and 15 minutes. The product was allowed to cool to room temperature and sit until precipitation of a dark green solid is complete. The reaction mixture is then filtered to give a dark green crystalline solid of the chloride salt of Cr3 (> 6.7 grams, > 55% yield).
This application is related to US Patents 5,872,102; 6,149,948; 6,197,816 and 6,444,231, and pending U.S. Patent Application Serial No. 11/392,503, the entire contents of each of which are hereby incorporated by reference.
Obviously, additional modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
Claims
1. A method for the synthesis of a chromium complex 2, [Cr3O(carboxylate)6(H2O)3]+ (2), wherein carboxylate is a substituted or unsubstituted C2-C5 alkyl carboxylate, comprising: heating an aqueous reaction mixture of a Cr(III) salt, a substituted or unsubstituted C2-C5 alkyl carboxylic acid and a metal hydroxide for a time period and at a temperature sufficient to generate an aqueous product mixture comprising chromium complex 2 and nontoxic byproducts.
2. The method of claim 1, further comprising separating the chromium complex 2 from the aqueous product mixture.
3. The method of claim 2, wherein the separating is performed by filtration or decanting.
4. The method of claim 1, wherein carboxylate is a member selected from the group consisting of acetate, propionate, n-butyrate and n-pentanoate.
5. The method of claim 4, wherein carboxylate is acetate or propionate.
6. The method of claim 5, wherein carboxylate is propionate.
7. The method of claim 1, wherein the Cr(III) salt is CrCl36H2O.
8. The method of claim 6, wherein the Cr(III) salt is CrCl36H2O.
9. The method of claim 1, wherein the metal of the metal hydroxide is an alkali metal or alkaline earth metal.
10. The method of claim 9, wherein the metal of the metal hydroxide is sodium, potassium or calcium.
11. The method of claim 10, wherein the metal of the metal hydroxide is sodium.
12. The method of claim 8, wherein the metal of the metal hydroxide is sodium.
13. The method of claim 1, wherein the molar ratio of Cr(III) saltalkyl carboxylic acid is in a range from 1 :2 to 1 : 100.
14. The method of claim 13, wherein the molar ratio of Cr(III) salt:alkyl carboxylic acid is approximately 1:2.
15. The method of claim 1, wherein the molar ratio of Cr(III) saltmetal hydroxide is in a range from 1 :2 to 1:3.
16. The method of claim 15, wherein the molar ratio of Cr(ITI) saltmetal hydroxide is approximately 1:2.
17. The method of claim 1, wherein the molar ratios of Cr(ITl) saltalkyl carboxylic acid:metal hydroxide are in a range from 1:2:2 to 1:3:100.
18. The method of claim 17, wherein the molar ratios of Cr(III) saltalkyl carboxylic acid:metal hydroxide are approximately 1:2:2.
19. The method of claim 12, wherein the molar ratios of CrCl36H2O propionic acid:sodium hydroxide are in a range from 1:2:2 to 1:3:100.
20. The method of claim 19, wherein the molar ratios of CrCl36H2O:propionic acid:sodium hydroxide are approximately 1:2:2.
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US3576762A (en) * | 1965-02-19 | 1971-04-27 | Inst Francais Du Petrole | Catalysts of modified basic trivalent metal acetates |
US5872102A (en) * | 1996-10-11 | 1999-02-16 | The University Of Alabama | Method for isolation of bovine low-molecular weight CR-binding substance and method of use of the same |
US6444231B2 (en) * | 1998-09-30 | 2002-09-03 | University Of Alabama | USE OF TRIAQUA-μ3-OXOHEXAKIS-μ-PROPIONATOTRICHROMIUM(1+), [CR3O(O2CCH2CH3)6(H2O)3]+, AS A NUTRITIONAL SUPPLEMENT OR IN TREATMENT OF MEDICAL CONDITIONS |
US20080033196A1 (en) * | 2006-08-04 | 2008-02-07 | Swee-Keng Goh | Metal carboxylate salts |
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US6149948A (en) * | 1999-07-02 | 2000-11-21 | University Of Alabama | Method of decreasing plasma cholesterol and triglycerides with a chromium-containing complex |
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2006
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2007
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Patent Citations (4)
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US3576762A (en) * | 1965-02-19 | 1971-04-27 | Inst Francais Du Petrole | Catalysts of modified basic trivalent metal acetates |
US5872102A (en) * | 1996-10-11 | 1999-02-16 | The University Of Alabama | Method for isolation of bovine low-molecular weight CR-binding substance and method of use of the same |
US6444231B2 (en) * | 1998-09-30 | 2002-09-03 | University Of Alabama | USE OF TRIAQUA-μ3-OXOHEXAKIS-μ-PROPIONATOTRICHROMIUM(1+), [CR3O(O2CCH2CH3)6(H2O)3]+, AS A NUTRITIONAL SUPPLEMENT OR IN TREATMENT OF MEDICAL CONDITIONS |
US20080033196A1 (en) * | 2006-08-04 | 2008-02-07 | Swee-Keng Goh | Metal carboxylate salts |
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US20080064894A1 (en) | 2008-03-13 |
US7405313B2 (en) | 2008-07-29 |
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